OBJECTIVE: Insulin resistance is associated with increased triglyceride levels, low high-density lipoprotein cholesterol, small dense low-density lipoprotein (LDL), and increased apolipoprotein B (apoB) levels, all characteristics of familial combined hyperlipidemia (FCH). Therefore, we explored the role of insulin resistance in FCH lipid phenotype expression. METHODS AND RESULTS: FCH was defined by traditional diagnostic criteria including plasma total cholesterol or triglyceride levels >90th percentile. Insulin resistance was assessed by the Homeostasis Model Assessment (HOMA) index. In total, 132 subjects with FCH, 350 normolipidemic relatives, and 81 spouses who referenced as controls were studied. FCH subjects were significantly more insulin resistant compared with controls and normolipidemic relatives (HOMA index 2.9 [95% CI, 2.6 to 3.2], 2.2 [95% CI, 2.0 to 2.5], and 2.0 [95% CI, 1.9 to 2.2], respectively), even after correction for sex, age, and body mass index (BMI). The degree of insulin resistance was associated with the lipid phenotype expression, and a change in insulin-resistant state was associated with a change in lipid phenotype expression over 5 years. For any level of insulin resistance and degree of obesity, FCH subjects had increased levels of apoB and more small dense LDL compared with controls. CONCLUSIONS: Insulin resistance is a characteristic feature of FCH, which is not fully explained by their increased BMI and is associated with (change in) lipid phenotype expression. Furthermore, our results support the concept of genetic origin of high apoB and small dense LDL in FCH, which is modulated by insulin resistance and obesity.